PROJECT SUMMARY To engage in productive social interactions, an animal must modulate its behavior based on the current situa- tion. Neural and genetic factors regulating homeostatic behaviors (e.g., feeding and sleeping) have been well studied, but the genetic mechanisms by which social behaviors are adjusted remain largely unexplored. Social behaviors are intrinsically more complex than homeostatic behaviors, because in a social context an animal must take into account its own internal state (e.g., hunger, arousal), as well as the reactions and perceived in- tentions of the other individual. Understanding how behavior-related neural circuits are modulated in these con- texts may shed light on human neural disorders that compromise patients' ability to interact with others (e.g., schizophrenia and autism). To identify genetic elements that correlate with behavioral phenotypes, genome- wide association studies have been performed involving patients with psychiatric disorders or animal models. Results from these approaches have been difficult to interpret, however, because: (1) most identified mutations had a small effect, 2) causality between mutation and behavioral phenotype often could not be established, and 3) mutations generally did not involve neuromodulators and neurohormonal systems known to control these processes. To develop more direct approaches for tackling this problem, researchers have turned to Drosophila melanogaster, which exhibits a rich repertoire of stereotypical social behaviors. The Drosophila sys- tem allows for precise genetic alterations, and the labeling and functional manipulation of specific cell types, making it an attractive model for studying how genes control behavioral choice by affecting specific neuronal populations. Research into fly agonistic behavior has been particularly informative, as specific neurons ex- pressing the neuropeptide tachykinin, which functions as a neuromodulator, have been shown to promote ag- gression. However, elements that dampen aggression levels have not been found. Using an RNAi screening approach, five genes that negatively regulate aggression were identified. Proposed research aims to elucidate the molecular mechanisms by which these genes control the intensity of agonistic interactions. These genes encode: (1) the neuropeptide FMRFamide, which may function as a neuromodulator to suppress agonistic be- havior, (2 and 3) PKA-R2 and nervy, which act downstream of G-protein coupled receptors and therefore may regulate signaling of aggression-promoting neuromodulators such as tachykinin, (4) TBPH, a transcriptional repressor implicated in neurodegenerative diseases, and (5) Gr21a, a CO2 co-receptor. Finally, interplay be- tween these negative regulators of aggression and known aggression promoters will be studied. As previous work on the genetics of Drosophila aggression has consistently identified genes that regulate mammalian ag- gression, the proposed project promises to illuminate genetic and neuronal networks that dynamically regulate agonistic interaction across animal phyla. Such knowledge will fill critical gap in our understanding about how genes influence social behaviors through specific neurons and circuits.